Jamaicamide B was isolated from the cyanobacterium Moorea producens in Jamaica and shows neurotoxicity as a sodium channel blocker. This unique mixed peptide-polyketide structure contains a pyrrolinone ring, a β-methoxy enone, an (E)-olefin, an undetermined stereocenter at C9, an (E)-chloroolefin, and a terminal alkyne. We report herein the first total synthesis and structural confirmation of the marine natural product (9S)-jamaicamide B.